Master Protocol Guidance in Cancer R&D: Impact on Industry

Jeffrey Hodge

In October 2018, the FDA released draft guidance for modernizing the approach to clinical trial design. “Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics” seeks to make clinical trials more efficient while maintaining patient safety and to increase the amount of information concerning product safety and benefits. With the guidelines still under review and the FDA expected to issue final guidance in late 2019 or early 2020, it is too soon to determine overall impact, but the hope is master protocol designs will help sponsors get creative and allow for more efficient and accelerated drug development.

In contrast to traditional trial designs, where a single drug is tested in a single disease population in one clinical trial, master protocols use a single infrastructure to evaluate multiple drugs in multiple substudies. The guidance describes master protocols for three types of trial design-basket, platform, and umbrella. Better engagement and communication between academia, industry, the National Cancer Institute (NCI), and the FDA is expected to broaden use of master protocols.  

When the draft guidance debuted, former FDA Commissioner Scott Gottlieb, MD, predicted “tissue-agnostic” clinical testing based on biomarkers like specific gene mutations would reduce development costs of targeted therapies and improve market competition.

FDA staff recently met with the NCI to begin work on facilitating communication between the FDA and clinical researchers early in the planning of master protocol drug development studies. NCI-MATCH, a precision medicine cancer treatment clinical trial, is testing the feasibility of basket trials across multiple sites. Patients are assigned to receive treatment based on genetic changes found in their tumors through tests like genomic sequencing. The trial is trying to determine whether treating cancer based on specific genetic changes is effective regardless of cancer type.

Traditionally, oncology trials have focused on treating cancer at a certain location in the body, such as breast or lung cancer. Basket studies include patients with a certain genetic mutation in common, regardless of the site or origin of cancer in the body. Basket studies can determine whether a drug targeting a certain genetic mutation at a particular site may effectively treat the same genetic mutation found in cancer at another site in the body.

In 2017, the FDA granted the first tissue-agnostic approval to pembrolizumab (Keytruda) for an expanded indication to treat microsatellite instability-high cancer based only on genetic abnormality, regardless of origin or location. A year later, the FDA approved larotrectinib (Vitrakvi) for adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation.

If trial sponsors pursue master protocol designs, the FDA has provided guidance for designing trials:

• If novel combinations of two or more investigational drugs are being explored, the master protocol should summarize available safety, pharmacology, and preliminary efficacy data for each investigational drug; the biological rationale for use of the drugs in combination instead of individually; and evidence, if any, of the drugs’ interaction when used together.

• If sponsors are investigating drugs that target multiple biomarkers, the master protocol should include a prespecified plan for allocating patients who are potentially eligible for multiple substudies.

• If sponsors seek to potentially add, expand, or discontinue treatment arms, sponsors should ensure that the master protocol and its associated statistical analysis plan describe conditions that would result in such adaptations.

• If sponsors anticipate utilizing the results from one or more of the substudies to support a marketing application, the master protocol should describe and provide the charter for independent data monitoring committees (IDMCs) to monitor efficacy and safety results. The charter should authorize these committees to conduct prespecified and ad hoc assessments of efficacy, safety, and futility and recommend protocol modifications or other appropriate actions (i.e., adjusting sample size or discontinuing the substudy based on futility or substantial evidence of efficacy).

• If pharmaceutical sponsors are utilizing master protocols to evaluate biomarker-defined populations, the master protocol should explain why use of the biomarker is appropriate and include a validated in vitro diagnostic test.

Incorporating master protocols into a clinical development program may reduce burdens associated with conducting separate studies and speed time to market. In the American Society of Clinical Oncology (ASCO) abstracts database for 2019, more than 25 studies are defined as basket, umbrella, or platform. All these trials were initiated prior to the master protocol guidance, thus the impact on sponsor adaptation to these new guidelines will be more greatly realized in 2020 and beyond.

Jeffrey Hodge, VP of Development Solutions and Head of Oncology Center of Excellence, IQVIA